Telomere dysfunction is known to play a large role in age related diseases such as cancer. Shortening of telomeres, localization of DNA damage response factors to telomeres, and DNA repair of telomeric double-strand breaks resulting in telomere deletions, telomere fusions, and telomere translocations can each serve as indicators of telomere dysfunction. High throughput next generation sequencing (HT-NGS) can permit direct analysis of genome structure. However current computational methods associated with HT-NGS fail to analyze repetitive regions such as telomeres and low-copy regions such as most subtelomeres; ambiguously mapping reads, such as those from telomere, and subtelomere regions, are not mapped to the reference sequence. These telomere and subtelomere reads are still available in the raw data set, but currently go unused. The Riethman lab has sequenced and characterized subterminal DNA segments from multiple unrelated human genomes, providing a unique reference set of sequences to which next-gen reads can be mapped. Their resources and infrastructure provide a unique training environment in which I can explore the use of next-gen datasets for the analysis of human telomere alterations, especially those known and expected to be associated with cancer. In completing the work outlined in this research plan I will become adept at cutting edge methods relating to HT-NGS and large data set manipulation and analysis. This will prepare me for a career investigating telomere biology and cancer using genome- wide experimental and computational approaches, and enable me to become an expert and make unique contributions to the field.